The major objective of the proposed research is to study the mechanism by which the expression of DNA is regulated. This will be done by injecting genes or modified genes into mouse ova. The effect of the DNA will be assayed in the ova following in vitro culture, or in mice that develop from the injected ova following transfer to foster mothers. The specific aims are: (1) Determine the nucleotide sequenes involved in regulation of metallothionein-1 gene transcription by heavy metals and glucocorticoids, (2) Determine the factors that influence the integration of genes into the genome following their injection into the nucleus of the fertilized one-cell mouse ovum and the expression of these genes in animals developing from the ova, (3) Determine whether a genetic defect in mice can be corrected by introducing appropriate genes determine what DNA sequences are important for regulation of a specific gene and should enable us to study the effect important biological changes, e.g. development and aging, have on the expression of several gene modification. In addition to the information we will obtain about gene regulation, the introduction of new genes into an animal will provide information of fundamental importance in determining the possible usefulness of gene therapy in the treatment of human disease.